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Hyperglycemia and Focal Brain Ischemia: Clinical and Experimental Studies
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Diabetes is a major risk factor for ischemic stroke and is associated with increased mortality. Additionally, hyperglycemia, a common complication in acute stroke, is associated with poor outcome.

In order to identify the correlation between blood glucose and early mortality, multiple logistic regression analyses were used and odds ratios calculated in a retrospective study of 447 stroke patients. Eighty-one patients (18%) had diabetes. The odds ratios for 30-day case-fatality and blood glucose were 1.9 and 1.6 in diabetic and non-diabetic patients respectively. Optimal blood glucose concentrations in respective group were 10.3 and 6.3 mmol/L, as determined by receiver operator characteristic (ROC) curves.

Cerebral ischemia triggers different signaling pathways including mitogen-activated protein kinases (MAPK) which regulate fundamental cell functions. In an experimental rat model of combined hyperglycemia and transient middle cerebral artery occlusion (MCAO), the activation pattern of one such MAPK, extracellular signal-regulated kinase (ERK) was studied along with infarct volumes and neurological function. Hyperglycemia resulted in markedly increased ERK activation and approximately three-fold increase of infarcts compared with controls.

Based on the increased ERK activation, further experiments were conducted to limit the hyperglycemic-ischemic damage by interfering with ERK and supposedly related mechanisms. Consequently, rats were given U0126 (inhibiting ERK activation), PBN (anti-oxidative), PP2 (inhibiting src-family kinases), or vehicle. PBN reduced infarcts and improved neurological function compared with controls while no statistically significant effects were observed for U0126 or PP2. However, when the dose was doubled, U0126 significantly reduced infarcts and improved neurological function after 1 day in hyperglycemic rats. Post-ischemic ERK activation was completely inhibited by U0126 as demonstrated with Western immunoblotting. The findings suggest that ERK is an important mediator of hyperglycemic-ischemic brain injury and possible target for future interventions.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2005. , p. 75
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 72
Keywords [en]
Internal medicine, cerebrovascular disorders, diabetes mellitus, hyperglycemia, infarction, middle cerebral artery, ischemia, mitogen-activated protein kinases, mortality, rats, reactive oxygen species, reperfusion, signal transduction, therapeutics
Keywords [sv]
Invärtesmedicin
National Category
Clinical Medicine
Identifiers
URN: urn:nbn:se:uu:diva-5938ISBN: 91-554-6345-2 (print)OAI: oai:DiVA.org:uu-5938DiVA, id: diva2:166983
Public defence
2005-10-14, Enghoffsalen, Ingång 50, Akademiska sjukhuset, Uppsala, 13:00
Opponent
Supervisors
Available from: 2005-09-23 Created: 2005-09-23Bibliographically approved
List of papers
1. Blood glucose in acute stroke, different therapeutic targets for diabetic and non-diabetic patients?
Open this publication in new window or tab >>Blood glucose in acute stroke, different therapeutic targets for diabetic and non-diabetic patients?
2005 In: Acta Neurol Scand, ISSN 16008532, Vol. 112, no 2, p. 81-7Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-93489 (URN)
Available from: 2005-09-23 Created: 2005-09-23Bibliographically approved
2. Differential Early Mitogen-activated Protein Kinase (MAPK) activation in hyperglycemic ischemic brain injury in the rat.
Open this publication in new window or tab >>Differential Early Mitogen-activated Protein Kinase (MAPK) activation in hyperglycemic ischemic brain injury in the rat.
2005 (English)In: Eur J Clin Invest, ISSN 16008548, Vol. 35, no 7, p. 457-63Article in journal (Refereed) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-93490 (URN)
Available from: 2005-09-23 Created: 2005-09-23 Last updated: 2015-06-10Bibliographically approved
3. Experimental treatment for focal hyperglycemic ischemic brain injury in the rat
Open this publication in new window or tab >>Experimental treatment for focal hyperglycemic ischemic brain injury in the rat
2005 (English)In: Experimental Brain Research, ISSN 0014-4819, E-ISSN 1432-1106, Vol. 167, no 2, p. 310-314Article in journal (Refereed) Published
Abstract [en]

Hyperglycemia aggravates ischemic brain injury, possibly due to the activation of signaling pathways involving reactive oxygen species, Src and mitogen-activated protein kinases. The aim of this study was to investigate the effects of the spin trap agent alpha-phenyl-N-tert-butyl nitrone (PBN), the Src family kinase inhibitor PP2 and the MEK1-inhibitor U0126 on focal hyperglycemic ischemic brain injury. Temporary middle cerebral artery occlusion (90 min) was induced in four groups of rats (PBN, PP2, and U0126 vs. control). Neurological testing and tetrazolium red staining were performed after 1 day. PBN decreased the infarct volume by 70% compared with the control (P<0.05) and a tendency towards reduced infarcts was seen in the PP2 or U0126 groups. Furthermore, neurological testing was consistent with the volumetric analysis. In conclusion, PBN appears to be a potential neuroprotective agent in hyperglycemic, focal ischemic brain injury, while the efficacy of PP2 and U0126 could not be confirmed by the present data.

Keywords
Animals, Blood Glucose/physiology, Body Temperature/physiology, Brain Ischemia/pathology/*prevention & control, Butadienes/therapeutic use, Carbon Dioxide/blood, Comparative Study, Enzyme Inhibitors/therapeutic use, Hyperglycemia/*complications/pathology, Male, Neurologic Examination/methods, Neuroprotective Agents/*therapeutic use, Nitriles/therapeutic use, Nitrogen Oxides/*therapeutic use, Oxygen/blood, Pyrimidines/therapeutic use, Rats, Rats; Sprague-Dawley, Research Support; Non-U.S. Gov't, Tetrazolium Salts/diagnostic use, Time Factors
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-93491 (URN)10.1007/s00221-005-0157-0 (DOI)16261339 (PubMedID)
Available from: 2005-09-23 Created: 2005-09-23 Last updated: 2017-12-14Bibliographically approved
4. The MEK-inhibitor U0126 in focal hyperglycemic ischemic brain injury in the rat
Open this publication in new window or tab >>The MEK-inhibitor U0126 in focal hyperglycemic ischemic brain injury in the rat
(English)Manuscript (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-93492 (URN)
Available from: 2005-09-23 Created: 2005-09-23 Last updated: 2015-06-10Bibliographically approved

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